Carlos A. Luciano

Quantitative analysis of epidermal innervation in Fabry disease

Objective: To use skin biopsy specimens to quantitate the cutaneous innervation density of Fabry patients who had preserved renal function. Background: The small fiber neuropathy of Fabry disease is difficult to detect and quantitate by conventional methods. Because this neuropathy is a common characteristic of Fabry disease, quantitating changes in this parameter would be helpful in demonstrating the effectiveness of enzyme or gene replacement therapy. Methods: Patients underwent skin biopsy at the thigh and foot. Innervation density was determined by counting free nerve endings in the epidermis. These data were compared with nerve conduction studies, and in selected patients, fiber quantitation of sural nerve biopsy specimens. Results: The Fabry patients had normal results of nerve conduction studies and large fiber quantitation by sural nerve biopsy. However, the involvement of small cutaneous fibers in these patients was easily demonstrable and quantifiable by skin biopsy. All patients showed severe loss of intraepidermal innervation at the ankle, but fiber loss at the distal thigh was proportionately less severe. Conclusions: The nerve damage in Fabry patients with preserved renal function involves exclusively small myelinated and unmyelinated fibers, and skin biopsy is a useful in detecting and quantitating such damage. Comparison of cutaneous innervation density with quantitation of sural nerve biopsy specimens demonstrated that skin biopsy specimens were as sensitive in detecting the presence of neuropathy as were the nerve specimens. It is speculated that analysis of cutaneous innervation may provide a useful marker of the nervous system’s response to specific therapy for Fabry disease.

Physiological characterization of neuropathy in Fabry's disease.

Fabrys disease is commonly associated with a painful, debilitating neuropathy. Characterization of the physiological abnormalities is an important step in evaluating response to specific therapies. Twenty‐two patients with Fabrys disease, and with relatively preserved renal function, underwent conventional and near‐nerve conduction studies, electromyography, sympathetic skin responses, and quantitative sensory testing (QST). Nerve conduction studies were mostly normal except for an increased frequency of median nerve entrapment at the wrist in 6 (27%) patients. Sympathetic skin responses were preserved in 19 of 20 (95%) of the patients. The QST showed increased or immeasurable cold and warm detection thresholds in patients, significantly different from controls (n = 28) in the hand (P < 0.001, P = 0.04, respectively) and foot (P < 0.001 for both). Cold thresholds were more often abnormal than were warm thresholds. Vibration thresholds were normal in the feet and, in some patients, elevated in the hand only, probably due to frequent median nerve entrapment at the wrist. Our findings suggest that the neuropathy of Fabrys disease is characterized by an increased prevalence of median nerve entrapment at the wrist and by thermal afferent fiber dysfunction in a length‐dependent fashion, with greater impairment of cold than warm sensation.

Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma

Polyclonal immunoglobulin M antibodies to the monosialoganglioside GM2, sulfoglucuronyl glycolipids, and sulfatide were detected by thin-layer chromatography and enzyme-linked immunosorbent assay in the serum of a patient with melanoma and chronic inflammatory demyelinating polyneuropathy. Both the patients serum and polyclonal antibodies against GM2 reacted strongly with a biopsy of melanomatous tissue from the patient, suggesting a process of molecular mimicry.

Cutaneous silent periods in patients with Fabry disease

We assessed the cutaneous silent period (CSP) in 24 patients with Fabry disease with small‐fiber sensory neuropathy and 12 normal subjects to test the hypothesis that small‐diameter afferents are responsible for producing the CSP. Sensory nerve conduction studies and quantitative sensory testing for cold and vibration detection thresholds were also measured. Overall, Fabry patients had impaired thermal, but not vibration, detection thresholds, with greatest impairment in the feet. In the upper extremity, CSP latencies, duration, and suppression of electromyographic activity (EMG) did not differ. In the lower extremity, patients had reduced suppression of EMG during the CSP compared to normal controls. CSP durations exhibited a bimodal distribution in patients, including a subset of seven patients with durations shorter than all controls. This subset had profound loss of thermal sensation in the feet, but this was also true of some patients who had normal CSPs. Patients with shortened CSPs had modestly elevated vibration thresholds and reduced sensory potentials in comparison to patients with normal CSPs. Reduced CSPs in Fabry patients are associated with, but not entirely explained by, the severity of small‐fiber neuropathy as measured by quantitative sensory testing. The possibility that large‐diameter fibers provide a minor contribution to producing the CSP should be considered.

Inclusion Body Myositis No Evidence for a Neurogenic Component

Because electrophysiologic, clinical, and histopathologic observations have suggested that inclusion body myositis (IBM) may have a coexistent neurogenic component, we used macro-electromyography (macro-EMG) to search for changes in the motor unit territory and signs of reinnervation. We studied 11 patients, aged 53 to 77 years (mean, 65.2 years), with typical, nonfamilial IBM lasting a mean of 8.5 years, and eight healthy volunteers aged 54 to 70 years (mean, 64.6 years), as control subjects. Nerve conduction studies showed focal abnormalities in 5 of the patients, but no evidence of a polyneuropathy. Concentric needle EMG in various proximal and distal muscles of the upper and lower limbs revealed short- or long-duration complex motor unit potentials (MUPs) or a mixture of both types of MUPs. Macro-EMG studies in the tibialis anterior muscle showed smaller macro-MUP amplitudes and areas in patients than in normal subjects. Four patients had abnormal macro-EMG studies with an increased number of small macro-MUPs, 1 patient had an equivocal study with large-amplitude but normal-area macro-MUPs, and the remaining 6 patients had normal studies. These findings are consistent with a primary muscle disorder similar to those seen in other myopathies. We conclude that macro-EMG does not support a coexistent neurogenic component in patients with IBM compared with normal subjects of similar age. NEUROLOGY 1997;48: 29-33

Nerve conduction abnormalities in aging mice deficient for myelin-associated glycoprotein.

Ultrastructural, biochemical, and electrophysiological analyses were done on 12–14‐month‐old mice deficient for myelin‐associated glycoprotein (MAG) to further characterize the neuropathy that develops as they age. Electron microscopy demonstrated normal myelin compaction and axonal degeneration in a large number of myelinated nerve fibers. Western blots showed that the proteins of compact myelin, P0 glycoprotein, and myelin basic protein were not significantly altered in the mutants; however, the Schwann cell protein, 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase, was reduced to less than half the control level. Also, both total and phosphorylated high‐molecular‐weight neurofilament proteins (TNFH and PNFH, respectively) were significantly decreased, as was the PNFH:TNFH ratio. Electrophysiological evaluation revealed a mild, but statistically significant, reduction of conduction velocity and a nonsignificant mild decrease in compound muscle action potential amplitudes. This constellation of findings in aging MAG‐null mice is consistent with an axonopathy that resembles axonal Charcot–Marie–Tooth (CMT2) disease in many respects. Thus, mutation of a myelin‐associated gene expressed by Schwann cells can induce axonal degeneration and cause a neuropathy with minimal signs of demyelination.

Electrophysiologic and histologic studies in clinically unaffected muscles of patients with prior paralytic poliomyelitis

Macro‐electromyography (macro‐EMG) studies have provided important information about the size of the motor units and the degree of reinnvervation in clinically affected muscles of patients with a history of poliomyelitis and postpolio syndrome. The study of clinically unaffected muscles and correlation of their electrophysiologic characteristics with the muscle architecture could provide meaningful information about the ongoing subclinical denervation. We performed macro‐EMG and concomitantly measured fiber density in the clinically unaffected gastrocnemius muscle of 10 patients with postpolio syndrome and 10 normal subjects of similar age. We also performed biopsies on the gastrocnemius muscle of 8 of the patients. The median amplitude and area of the macro‐motor unit potentials (macro‐MUPs) were increased in 8 of the 10 patients, and occasionally were five times as large as the mean median value for the normal subjects. Seven biopsy specimens showed moderate to very large fiber‐type grouping. In 5 patients, there was correlation between the electrophysiologic and histologic indices of reinnervation. Amplitude and area of the macro‐MUPs were associated with the muscle fiber cross‐sectional area. We conclude that clinically unaffected muscles of patients with postpolio syndrome often have large motor units as the result of effective reinnervation after the original motor neuron loss. In spite of possible differences in the cytoarchitecture of muscles affected to different degrees, macro‐EMG and fiber density measurements are reliable noninvasive techniques for studying the extent and effectiveness of reinnervation in patients with postpolio syndrome.

Peripheral neuropathy in children with HIV infection

Peripheral neuropathy is infrequently reported in children with HIV infection, but may be underrecognized. To provide a better understanding of the patterns of peripheral neuropathy in these children, we surveyed the charts of 50 children with HIV infection referred to the EMG laboratory at the National Institutes of Health for evaluation of suspected peripheral neuropathy. Twelve children had an abnormal nerve conduction study. The findings suggested a distal sensory or sensorimotor axonal neuropathy in seven children, median nerve compression at the carpal tunnel in three, a demyelinating neuropathy in one child, and a lumbosacral polyradiculopathy in one adolescent. Distal symmetric polyneuropathy occurred mostly in older-aged children.